iTRAQ proteomics analysis reveals that PI3K is highly associated with bupivacaine-induced neurotoxicity pathways
iTRAQ proteomics analysis reveals that PI3K is highly associated with bupivacaine-induced neurotoxicity pathways
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iTRAQ 蛋白质组学分析表明 PI3K 与布比卡因诱导的神经毒性途径高度相关。
DOI：
10.1002/pmic.201500202
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发表时间：
2016-02-01
期刊：
影响因子：
3.4
通讯作者：
Xu, Shi-yuan
中科院分区：
文献类型：
--
作者：
Zhao, Wei;Liu, Zhongjie;Xu, Shi-yuan
布比卡因是一种常用的局麻药，通过不同的信号通路具有潜在的神经毒性。然而，布比卡因神经毒性的关键机制仍不清楚。用布比卡因处理SH-SY5Y神经母细胞瘤细胞24 h，与对照组相比，布比卡因显著增加细胞抑制、细胞内氧自由基、DNA损伤、线粒体损伤、细胞凋亡(TUNEL阳性细胞、裂解caspase3和Bcl2/Bax增加)和激活自噬(提高Lc3II/Lc3I比值)。为了探讨布比卡因神经毒性过程中蛋白表达和相互通讯的变化，应用8-plex iTRAQ蛋白质组学技术和生物信息学分析。与对照组相比，共鉴定出241个差异表达蛋白，其中145个上调，96个下调。生物信息学分析表明，在布比卡因诱导的神经毒性中，表达改变的重要蛋白之间的相互作用表明，磷脂酰3-激酶(PI3K)是每种相互作用中最常见的靶蛋白。我们通过确定已识别的信号通路(PI3K、Akt、FoxO1、Erk和JNK)的下游靶标进一步证实了这些结果。总之，我们的研究表明，PI3K可能在联系和调节导致布比卡因神经毒性的信号通路中发挥核心作用。
Bupivacaine, a commonly used local anesthetic, has potential neurotoxicity through diverse signaling pathways. However, the key mechanism of bupivacaine-induced neurotoxicity remains unclear. Cultured human SH-SY5Y neuroblastoma cells were treated (bupivacaine) or untreated (control) with bupivacaine for 24 h. Compared to the control group, bupivacaine significantly increased cyto-inhibition, cellular reactive oxygen species, DNA damage, mitochondrial injury, apoptosis (increased TUNEL-positive cells, cleaved caspase 3, and Bcl-2/Bax), and activated autophagy (enhanced LC3II/LC3I ratio). To explore changes in protein expression and intercommunication among the pathways involved in bupivacaine-induced neurotoxicity, an 8-plex iTRAQ proteomic technique and bioinformatics analysis were performed. Compared to the control group, 241 differentially expressed proteins were identified, of which, 145 were up-regulated and 96 were down-regulated. Bioinformatics analysis of the cross-talk between the significant proteins with altered expression in bupivacaine-induced neurotoxicity indicated that phosphatidyl-3-kinase (PI3K) was the most frequently targeted protein in each of the interactions. We further confirmed these results by determining the downstream targets of the identified signaling pathways (PI3K, Akt, FoxO1, Erk, and JNK). In conclusion, our study demonstrated that PI3K may play a central role in contacting and regulating the signaling pathways that contribute to bupivacaine-induced neurotoxicity.